Limb loss from vascular disease, trauma, and cancer currently affects nearly 2 million Americans. It is a devastating, life-altering condition for which no satisfactory treatment exists. A major obstacle in the creation of high-functioning neuroprosthetics is the lack of neural interfaces that efficiently convey both motor and sensory information between the host nervous system and peripheral robotic devices. The long-term objective of this project is the development of such an interface utilizing the peripheral nervous system as the site of interaction with a neuroprosthetic. This approach seeks to exploit the inherent processing power of the central nervous system and to minimize injury to healthy tissues that are accessed by existing interface technologies, such as brain and muscle. In order to create a novel neural interface based on the peripheral nervous system, this proposal employs a hybrid neuronal-electronic construct to connect with host neurons. This construct consists of mechanically elongated axonal tracts integrated with a microelectrode array. As opposed to the insertion of electrodes into peripheral nerves, the proposed strategy relies upon a biological interface with the host nervous system, which provides the significant advantage of long-term contact stability between the components of the interface. Two specific aims are targeted using the proposed hybrid-construct approach. First, the mechanisms of integration between the neuronal element of the hybrid construct and host neurons are explored. This integration is hypothesized to occur via either axon-guided regeneration of host axons or synaptic integration. Methods for differentiating these two possibilities include fluorescence immunohistochemistry for markers of axonal regeneration and synapse formation and direct measurements of host axonal growth. Second, the extent of functional integration between the hybrid construct and the host nervous system is investigated. The transmission of action potentials along the hybrid construct initially is examined in vitro. Subsequent in vivo studies assess the transmission of electrical activity to and from the host peripheral and central nervous systems, the latter involving motor cortex stimulation and mapping of somatosensory potential equivalents evoked by the microelectrode array. Techniques for enhancing functional integration may include the concurrent transplantation of glial cells and the infusion of trophic factors. Achieving the objectives of this project establishes the feasibility of a neural interface that interacts biologically with the peripheral nervous system. In the short-term, these results would provide the foundation for work to decode signals recorded by the hybrid-construct microelectrode array, which could then be used to drive simple robotic tasks. Long-term, successful completion of this project would create a new avenue for research into a viable neural interface with advanced neuroprosthetics.